RESEARCH Open Access Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage: an updated systemic review and meta-analysis George KC Wong 1* , Ronald Boet 2 , Wai S Poon 1 , Matthew TV Chan 3 , Tony Gin 3 , Stephanie CP Ng 1 , Benny CY Zee 4 Abstract Introduction: Previous meta-analyses of magnesium sulphate infusion in the treatment of aneurysmal subarachnoid hemorrhage (SAH) have become outdated due to recently published clinical trials. Our aim was thus to perform an up-to-date systemic review and meta-analysis of published data on the use of magnesium sulphate infusion in aneurysmal SAH patients. Methods: A systemic review and meta-analysis of the literature was carried out on published randomized controlled clinical trials that investigated the efficacy of magnesium sulphate infusion in aneury smal SAH patients. The results were analyzed with regard to delaye d cerebral ischemia (DCI), delayed cerebral infarction, and favorable neurological outcomes at three and six months. The risks of bias were assessed using the Jadad criteria, with a Jadad score >3 indicating a lower such risk. Meta-analyses are presented in terms of relative risk (RR) with 95% confidence intervals (CIs). Results: Six eligible studies with 875 patients were reviewed. The pooled RR for DCI was 0.87 (95% CI, 0.36 to 2.09; P = 0.75). That for delayed cerebral infarction was 0.58 (95% CI, 0.35 to 0.97; P = 0.04), although this result did not persist if only randomized clinical trials with a lower risk of bias were included (RR 0.61, 95% CI, 0.31 to 1.22; P= 0.17). The pooled RR for a favorable outcome at three months was 1.14 (95% CI, 0.99 to 1.31; P = 0.07), and that for a favorable outcome at six months was 1.08 (95% CI, 0.94 to 1.24; P = 0.29). Conclusions: The present findings do not lend support to a beneficial effect of magnesium sulphate infusion on delayed cerebral infarction. The reduction in DCI and improvement in the clinical outcomes of aneurysmal SAH patients following magnesium sulphate infusion observed in previous pilot studies are not confirmed, although a beneficial effect cannot be ruled out because of sample size limitation. Introduction Although spontaneous subarach noid hemorrha ge (SAH) accounts for only 3 to 5% of all strokes and 4.4% of deaths from stroke [1,2], the relative youth of the indivi- duals affected means that it is actually responsible for approximately 25% of all years of life lost as a result of stroke [3]. Such complications as early brain injury and delayed ischemic neurological deficits remain a major cause of morbidity and mortality in this group of patients. Pilot clinical trials using magnesium sulphate in patients with acute aneurysmal SAH have reported a trend toward a reduction in clinical deterioration due to delayed cerebral ischemia (DCI) and an improvement in clinical outcomes [4-11], although two recently com- pleted clinical trials failed to demonstrate any im prove- ment in neurological outcomes [12,13]. Interestingly, however, a German trial found a significant decrease in delayed cerebral infarction but no improvement in neu- rological outcomes, in contrast to other retrospective analyses [13-15]. Previous meta-analyses of the use of magnesium sul- phate infusion to treat aneurysmal SAH have become outdated due to recently published clinical trials [16-18]. Hence, we conducted an up-to-date literature review * Correspondence: georgewong@surgery.cuhk.edu.hk 1 Division of Neurosurgery, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Road, Shatin, NT, Hong Kong SAR, PR China Full list of author information is available at the end of the article Wong et al. Critical Care 2011, 15:R52 http://ccforum.com/content/15/1/R52 © 2011 Wong et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reprod uction in any medium, provided the original work is properly cited. and meta-analysis of published data on patients with DCI, delayed cerebral infarction, or neurological outcomes. Materials and methods Type of studies We included only randomized controlled clinical trials comparing magnesium sulphate infusion to plac ebo infusion for patients with acute aneurysmal SAH. Types of outcome measures The primary outcome was dichotomized neurological outcome using Glasgow Outcome Scale (GOS) [19] and modified Rankin Scale (mRS) [20] at three and six months. We also assessed surrogate outcome with DCI and delayed cerebral infarction according to a recent consensus paper [15]. Definition of outcome measures In our systemic review and meta-analysis, DCI was defined as the occurrence of: clinical deterioration, which was manifested clinically as a new focal neurolo- gical deficit (motor or speech deficit) that developed after SAH or a decrease in the Glasgow Coma Scale of two or more points for more than six hours; and/or delayed cerebral infarction, which was defined as a new cerebral infarction within three weeks that was not related to post-treatment (coiling or clipping) complica- tions, the ventricular catheter track, a rebleed, or hydro- cephalus [15]. Another outcome, delayed cerebral infarction, was similarly defined as a new cerebral infarction within three weeks that was not related to post-treatment (coil- ing or clipping) complications, the ventricular catheter track, a rebleed, or hydrocephalus. Neurological outcomes were defined by the GOS [19] and mRS [20]. A favorable outcome was defined as a GOS score of 4 to 5 or a mRS score of 0 to 2. Search strategy Cochrane Central Register of Controlled Trials (Clinical Trials), EMBASE, PubMed, and Ovid MEDLINE searches (using the keywords magnesium AND subar- achnoid hemorrhage) of studies employing randomized contro lled trials and published between 1 Janu ary, 198 0 and 15 June, 2010 were carried out. The refere nces listed in these publications were also searched for rele- vant studies. Risk of bias assessment The Jadad criteria were used to assess the risk of bias [21]. The criteria included randomization, blinding, and an explanation of withdrawal or lo ss to follow up. Clini- cal trials with Jadad scores of 3 or above were considered to be of high quality. No funnel plot was employed to test for asymmetry, beca use fewer than 10 clinical trials were ultimately included. Statistical analysis Statistical analyses were generated using SPSS for Win- dows Version 15.0 (SPSS Inc., Chicago, Illinois, USA) and Review Manager 5 (Cochrane Collaboration, Oxford, UK). Statistical significance was taken as a P value less than 0.05 or a 95% confidence interval (CI) of relative risk (RR) not including 1. Data are represented using numbers (percentages) for the categorical variables and mean +/- standard deviations for the numerical variables. The I 2 value for heterogeneity describes the proportion of total variation in a study estim ated to be due to het- erogeneity. The random-effects model was employed to pool studies when statistical heterogeneity occurred (the P value was le ss than 0.1) or when the I 2 value was larger than 0.3; otherw ise, the fixed-effects m odel was used. Results are presented using the RRs and 95% CIs. Results Search results A PubMed literature search (using the keywords magne- sium AND subarachnoid hemorrhage) of studies employing randomized controlled trials and published between 1 January, 1980 and 15 June, 2010 yielded 20 publications. Additional searches of the Cochrane Cen- tral Register of Controlled Trials (Clinical Trials), EMBASE, and Ovid MEDLINE (using the keywords magnesium AND subarachnoid hemorrhage and consid- ering only human studies) yielded 51, 72, and 91 publi- cations, respectively. The references listed in these publications were also searched for relevant studies. Examination of the abstracts and/or manuscripts revealed seven completed randomized controlled clinical trials on the use of magnesium in patients with aneurys- mal SAH [6,8-13] and one methodology-only abstract [22]. None of these studies detected a statistically signifi- cant improvement in primary clinical outcome measures. Study descriptions Veyna and colleagues [6] reporte d the results of a 40-patient prospective single-blinded clinical trial of high-dose magnesium sulphate infusion therapy (a bolus of 6 g followed by 2 g per hour intravenous infusion, with a target magnesium level of 4 to 5.5 mg/dl) follow- ing spontaneous SAH. They enrolled patients with Hunt and Hess grades II to IV at admission and presenting within 72 hours after spontaneous SAH. In the magne- sium treatment group, they maintained the magnesium sulphate infusion for 10 days. They presented no data on DCI or delayed cerebral infarction. A favorable Wong et al. Critical Care 2011, 15:R52 http://ccforum.com/content/15/1/R52 Page 2 of 8 outcome (good recovery o r moderate disability, as defined by GOS 4 to 5) was achieved in 13 of 20 (65%) patients receiving magnesium sulphate infusion and 10 of 20 (50%) patients receiving the placebo treatment. No data were available for excellent outcome (good recov- ery, as defined by GOS 5 or mRS 0 to 1). Van den Bergh and colleag ues [8] reported the magne - sium group results for the Magnesium and Acetylsalicylic Acid in Subarachnoid Hemorrhage (MASH) trial, a ran- domized, double-blinded, placebo-controlled multicenter trial with a factorial design. The salicylic acid-related data were not complete at this stage. A total of 283 patients were randomized within four days of aneurysmal SAH. Magnesium treatment consis ted of a conti nuous intrave- nous dose of 64 mmol/day, begun within four days of SAH and continued until 14 days after occlusion of the aneurysm. CT hypointensities (with clinical features of a decreased consciousne ss level or new focal neurological deficit) occurred in 22 of 139 (16%) magnesium-treated patients and 35 of 144 (24%) placebo-treated patients, but no data were made available for DCI and delayed cer- ebral infarction according to the recent consensus paper [15]. Unfavorable outcomes occurred in 38 of 139 (27%) magnesium-treated patients and 51 of 144 (35%) pla- cebo-treated patients. There were no separate outcome data on excellent outcomes. In our single-center pilot study [9], 60 patients were randomly allocated to receive either magnesium sul- phate infusion (80 mmol/day) or saline infusion for 14 days. We did not record DCI or cerebral infarction as a separate outcome measure during this pilot study. A favorable outcome was achieved in 20 of 30 (67%) patients receiving magnesium sulphate infusion and 16 of 30 (53%) patients receiving the placebo treatment, and an excellent outcome in 14 of 30 (47%) of the for- mer and 10 of 30 (33%) of the latter. Muroi and colleagues [11] reported the results of a prospective, randomized, patient-blinded, placebo-con- trolled pilot study of 58 patients with aneurysmal SAH predominantly treated by microsurgical clipping (97%). The patients allocated to the treatment group received a bolus of 16 mmol magnesium sulphate administered over 15 minutes, followed by a continuous intravenous infusion of 64 mmol per day for 14 days. To maintain the serum magnesium level at twice the baseline, with a maximum of 2.0 mmol/L until the 14th day after SAH, subsequent dosage adjustments were made every 12 hours. Delayed cerebral infarction occurred in 3 of 31 (10%) patients in the treatment group and 6 of 27 (22%) in the placebo group. A favorable neurological outcome was achieved in 20 of 31 (64%) patients in the treatment group and 13 of 27 (48%) in the placebo group, and an excellent outcome was achieved in 18 of 31 (58%) in the former and 12 of 27 (44%) in the latter. The Asian-Australasian Intravenous Magnesium Sul- phate for Aneurysmal Subarachnoid Hemorrhage (IMASH) trial was a randomized, double-blinded, pla- cebo-controlled, multicenter phase III trial [12], under the protocol of which patients who were diagnosed with acute aneurysmal SAH (within 48 hours of ictus) were randomly assigned to receive either intravenous magne- sium sulphate infusion or normal saline infusion (pla- cebo). For patients receiving the active treatment, 20 mmol of magnesium sulphate was administered over 30 minutes, followed by a continuous infusion of 80 mmol of magnesium sulphate per day for up to 14 days after the hemorrhage. The plasma magnesium concentra- tion was measured regularly. The infusion was adjusted to raise the plasma magnesium concentration t o approxi- mately twice the baseline value and less than 2.5 mmol/L. The patients in the control group received an equivalent volume of normal saline. The proportions of patients with a favorable outcome were similar: 108 of 169 (64%) in the magnesium sulphate group and 100 of 158 (63%) in the saline group. So too were those with an excellent outcome: 77 of 169 (46%) in the magnesium sulphate group and 71 of 158 (45%) in the saline group. The proportions of patients with DCI and delayed cerebral infarction were also similar. Westermaier and colleagues [13] recently reported the results of another single-center, randomized controlled clinical trial. Patients were randomly allocated to receive either magnesium sulphate infusion (with a target level of 2.0 to 2.5 mmol/L) or saline infusion for 14 days. This study reported negative clinical outcomes, but showed a reduction in DCI and delayed cerebral infarction with magnesium sulphate infusion. A favorable outcome was reported for 34 of 54 (63%) patients in the treatment group and 27 of 53 (51%) in the placebo group, and an excellent outcome for 27 of 54 (50%) in the former an d 18 of 53 (34%) in t he latter. DCI occurred in 20 of 53 (37%) patients in the magnesium group and 35 of 53 (66%) in the control group. Delayed cerebral infarction occurred in 12 of 54 (22%) patients in the magnesium group and 27 of 53 (51%) in the control group. Ourpilotstudy[9],IMASH[12],themagnesium component of the MASH study [8], and the studies pub- lished by Veyna and colleagues [6], Muroi and collea- gues [11], and Westermaier and colleagues [13] were analyzed. The study by Schmid-Elsasser and colleagues [10] was excluded because of the unconventional omis- sion of nimodipine in the magnesium group. That by Pravedello and colleagues [23] was excluded from the analysis because no measures of DCI, cerebral infarc- tion, or clinical outcomes were reported . The six eligible studies were reviewed according to the terminologies defined in the Met hods section (Table 1) The target of the magnesium arm of the six studies was to produce a Wong et al. Critical Care 2011, 15:R52 http://ccforum.com/content/15/1/R52 Page 3 of 8 similar degree of hypermagnesemia, namely, double the baseli ne value. All of the studies recruited pati ents with SAH during the acute phase, within 48 to 96 hours of the aneurysmal SAH. The magnesium infusion was maintained for 10 to 14 days, and the neurological out- come was measured using the GOS or mRS at three months [6,8,11] or six months [9,12,13], but not both. Assessment of risks of bias in included studies The six eligible studies were assessed for risks of bias using the Jadad criteria (Table 2). Four of the six trials were found to have lower bias risks (Jadad score above 3) [8,9,12,13 ]. The authors of this systemic review acknowl- edged potential risk of bias because we were authors of two of the included studies in this systemic review [9,12]. Meta-analysis of eligible randomized clinical trials with relevant data available according to the consensus paper definitions Two studies with 434 patients were available for analysis of DCI. The pooled RR for DCI was 0.87 (95% CI = 0.36 to 2.09; P = 0.75; Figur e 1). Three studies with 492 patients were available for analysis of delayed cerebral infarction. The pooled RR for delayed cerebral infarction was 0.58 (95% CI = 0.35 to 0.97; P =0.04;Figure2) [15]. Three studies with 381 patients and 3 studies with 494 patients were available for analyses of favorable outcome at three months and six months, respectively. The pooled RR for a favorable outcome at three months was 1.14 (95% CI = 0.99 to 1.31; P = 0.07; Figure 3), and that for a favorable outcome at six months was 1.08 (95% CI = 0.94 to 1.24; P = 0.29; Figure 4). When only the four high-quality randomized clinical trials (those with a Jadad score above 3) were consid- ered, two studies with 434 patients were available for analysis of DCI. The beneficial effect on delayed cerebral infarction did not persist ( RR = 0.61, 95% CI = 0.31 to 1.22; P = 0.17; Figure 5), although the other outcomes remained statistically similar. Discussion The results of our up-to-dat e meta-analysis suggest that the present findings do not lend support to a beneficial Table 1 Outcome parameters of the randomized controlled clinical trials included Trial Patient number Serious adverse events Delayed cerebral ischemia Delayed cerebral infarction Three-month favorable outcome Three-month excellent outcome Six-month favorable outcome Six-month excellent outcome Veyna 2002 [6] 40 No No No Yes No No No van den Bergh 2005 [30] 283 Not mentioned No No Yes No No No Wong 2006 [9] 60 No No No No No Yes Yes Muroi 2008 [11] 58 Hypotension (12), cardiac events (4) No Yes Yes Yes No No Westermaier 2010 [13] 107 Hypocalcemic tetany (1) Yes Yes No No Yes Yes Wong 2010 [12] 327 Limb weakness (1), severe electrolyte disturbance (1) Yes Yes No No Yes Yes The terminologies for delayed cerebral ischemia, delayed cerebral infarction, and favorable and excellent outcome are defined in the Materials and methods section. Table 2 Quality assessment of the randomized controlled clinical trials included Trial Center Randomization method Blind Explanation for withdrawals Jadad Scale Veyna 2002 [6] Monocenter Not stated Patients were blinded Yes 2 van den Bergh 2005 [30] Multicenter Study medications were randomized and distributed by coordinating center Principal investigators and assessors were blinded Yes 4 Wong 2006 [9] Monocenter Sealed envelopes in order Assessors and health care staff were blinded Yes 4 Muroi 2008 [11] Monocenter Not stated Patients were blinded Yes 2 Westermaier 2010 [13] Monocenter Enveloped lot from a box Assessors were blinded Yes 4 Wong 2010 [12] Multicenter Randomization through Internet/sealed envelopes in order Patients, assessors, and health care staff were blinded Yes 4 Wong et al. Critical Care 2011, 15:R52 http://ccforum.com/content/15/1/R52 Page 4 of 8 Figure 1 Random-eff ect s model of risk ratio for delayed cerebral ischemia in aneurys mal subarachnoid hemorrhage patients given magnesium sulphate infusion and a placebo: a comparison [12,13]. Figure 2 Random-effects model of risk ratio for delayed cerebral infarction in aneurysmal subarachnoid hemorrhage patients given magnesium sulphate infusion and a placebo: a comparison [11-13]. Figure 3 Fixed-effects model of risk ratio for a favorable outcome at three months: a comparison between magnesium sulphate infusion and a placebo in patients with aneurysmal subarachnoid hemorrhage [6,11,30]. Figure 4 Fixed-effects model of risk ratio for a favorable outcome at six months: a comparison between magnesium sulphate infusion and a placebo in patients with aneurysmal subarachnoid hemorrhage [9,12,13]. Wong et al. Critical Care 2011, 15:R52 http://ccforum.com/content/15/1/R52 Page 5 of 8 effect of magnesium sulphate infusion in reducing DCI and leading to better clinical outcome. Some would argue that these negative findings could be due to a lack of tight neuro-intensive monitoring and treatment, thereby resulting in variation in management outcomes and diluting the neuro-protective effects of magnesium sulphate infusion [24]. However, whether tight para- meter control, such as glycemic control, would result in better neurological outcomes remains debatable [24]. The recent meta-analysis by Ma and colleagues sug- gested that intravenous magnesium therapy reduced the risk of DCI and poor outcome after aneurysmal SAH [18]. However, they have not taken into account the widely varied outcome definitions and time points among studies and simply pooled for assessments. Moreover, two more studies had been published since the meta-analysis by Ma and colleagues. The Asian- Australasian IMASH study was the first international multi-center randomized controlled clinical trial in test- ing the efficacy of intravenous magnesium sulphate infu- sion in aneurysmal SAH with negative results in all clinical and surrogate outcomes [12]. Westermaier and colleagues found a significant 29% decrease in delaye d cerebral infarction and a nonsignificant 9% decrease in unfavorable outcomes with magnesium sulphate infusion [13]. However, in the landmark British aneurysm nimo- dipine trial and recently published IMASH report, the differences in th e proportions of delayed cerebral infarc- tion paralleled those in the propo rtions of favorable out- comes [12,25]. Whether these decreases represent a change in the pattern of detected delayed cerebral infarction with the evolution of endovascular treatment and neuro-intensive care remains to be investigated. There are seve ral limitations to the meta-a nalysis pre- sented in this paper. The regimens of magnesium sul- phate infusion varied across t he different studies, and caution should thus be exercised in extrapolating the results. Oth er problems include the wide variation in the definitions of outcome measures and the time points of assessment, making a smaller number of studies available for meta-analyses of different outcome measures. Furthermore, there may be a publication bias toward the reporting of positive trends and spuriously inflated effects in smaller studies. Statistical heterogeneities were noted in the me ta-analyses for DCI and delayed cerebral infarc- tion. The risk of bias was assessed with Jadad criteria [22]; the other option would have been to employ domain-based evaluation [26]. However, any proposed tool wo uld have difficulties to validate, and real istic assessment is eventually open to subjectivity. The recent consensus is that cerebral infarction on plain computed tomography (CT) scan is the most objective measure of DCI, based on the British Aneurysm Nimodipine Trial and other retrospective analyz es [15,5], in which the data were obtained primarily from microsurgically treated intracranial aneurysms. However, identifying dela yed cer- ebral infarct ion from among all causes of CT hypointen- sities can be difficult with plain CT alone [27]. Although our post-hoc analysis of the IMASH data did not suggest a higher achieved plasma magnesium con- centration to be associated with a better clinical outcome [28], the current evidence suggests that the development of a clinical trial targeting reductions in s ymptomatic vasospasm and cerebral infarction, and an improvement in clinical outcomes, would require a large sample size (as many as 2,445 patients) to demonstrate the efficacy of such treatment in improving neurological outcomes, even with a treatment effect size of 50% [29]. Finally, the relatively small number of patients in the present meta- analysis could mask a possible smaller beneficial effect of magnesium sulphate i nfusion. Another European multi- center trial (Magnesium in Aneurysmal Subarachnoid Hemorrhage: MASH II) employing a slightly lower dosage regimen is ongoing and should contribute further data for future meta-analysis of the use of magnesium sulphate infusion in patients with aneurysmal SAH [30]. Conclusions The reduction in DCI and improvement in clinical out- comes for aneurysmal SAH patients with magnesium Figure 5 Random-effects model of risk ratio for delayed cerebral infarction: a comparison between magnesium sulphate infusion and a placebo in patients with aneurysmal subarachnoid hemorrhage (trials with a Jadad score above 3 included) [12,13]. Wong et al. Critical Care 2011, 15:R52 http://ccforum.com/content/15/1/R52 Page 6 of 8 sulphate infusion observed in previous pilot studies has not been confirmed although a beneficial effect cannot be ruled out because of sample size limitation. Key messages • Pilot studies have suggested the possible beneficial effects of magnesium sulphate infusion in treating patients with aneurysmal SAH, but previous meta- analyses have become outdated by recently published clinical trials. • An up-to-date systemic review and meta-analysis showed that magnesium sulphate infusion does not reduce DCI or improve neurological outcomes although a beneficial effect cannot be ruled out because of sample size limitation. Abbreviations CI: confidence interval; CT: computed tomography; DCI: delayed cerebral ischemia; GOS: Glasgow Outcome Scale; IMASH: Intravenous Magnesium Sulphate for Aneurysmal Subarachnoid Hemorrhage trial; MASH: Magnesium and Acetylsalicylic Acid in Subarachnoid Hemorrhage trial; MASH: Magnesium and Acetylsalicylic Acid in Subarachnoid Hemorrhage; mRS: modified Rankin Scale; RR: relative risk; SAH: subarachnoid hemorrhage. Acknowledgements We would especially like to thank the patients and their relatives who agreed to participate in the clinical trials discussed herein, as well as all of the medical and nursing staff in the participating centers who supported these trials. The IMASH trial was partly supported by the Research Grants Council of Hong Kong [CUHK Ref. No. CUHK4183/02M]. IMASH was approved by the CUHK-NTEC Clinical Research Ethics Committee [CRE-2002.078-T], and informed written consent was obtained from all IMASH patients participating in the study and for the publication of the manuscripts, tables and/or figures. Copies of their written consent forms are available for review from the editor-in-chief of Critical Care. Author details 1 Division of Neurosurgery, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Road, Shatin, NT, Hong Kong SAR, PR China. 2 Surgical Services, St. George’s Hospital, 249 Papanui Road, Strowan, Christchurch 8014, New Zealand. 3 Department of Anesthesia and Intensive Care, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Road, Shatin, NT, Hong Kong SAR, PR China. 4 School of Public Health, Prince of Wales Hospital, The Chinese University of Hong Kong, 30- 32 Ngan Shing Road, Shatin, NT, Hong Kong SAR, PR China. Authors’ contributions All of the authors contributed to the design of the study. GKW, SCN, and BZ were responsible for the statistical analysis. GKW drafted the manuscript. All of the authors critically revised the manuscript and agreed on the submitted version. Competing interests The authors declare that they have no competing interests. Received: 22 November 2010 Revised: 6 January 2011 Accepted: 7 February 2011 Published: 7 February 2011 References 1. Sudlow CL, Warlow CP: Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. Stroke 1997, 28:491-499. 2. Wong GK, Ng RY, Poon WS: Aneurysmal subarachnoid haemorrhage. Surgical Practice 2008, 12:51-55. 3. Johnston SC, Selvin S, Gress DR: The burden, trends, and demographics of mortality from subarachnoid hemorrhage. Neurology 1998, 50:1413-1418. 4. Boet R, Mee E: Magnesium sulphate in the management of patients with Fisher grade 3 subarachnoid hemorrhage: a pilot study. Neurosurgery 2000, 47:602-607. 5. Chia RY, Hughes RS, Morgan MK: Magnesium: a useful adjunct in the prevention of cerebral vasospasm following aneurysmal subarachnoid hemorrhage. J Clin Neurosci 2002, 9:279-281. 6. Veyna RS, Seyfried D, Burke DG, Zimmerman C, Mlynarek M, Nichols V, Marrocco A, Thomas AJ, Mitsias PD: Magnesium sulphate therapy after aneurysmal subarachnoid hemorrhage. J Neurosurg 2002, 96:510-514. 7. van den Bergh WM, Albrecht KW, Berkelbach van der Sprenkel JW, Rinkel GJ: Magnesium therapy after aneurysmal subarachnoid haemorrhage: a dose-finding study for long term treatment. Acta Neurochir (Wien) 2003, 145:195-199. 8. van den Bergh WM, on behalf of the MASH Study Group: Magnesium sulphate in aneurysmal subarachnoid hemorrhage. Stroke 2005, 36:1011-1015. 9. Wong GK, Chan MT, Boet R, Poon WS, Gin T: Intravenous magnesium sulphate after aneurysmal subarachnoid hemorrhage: a prospective randomized pilot study. J Neurosurg Anesthesiol 2006, 18:142-148. 10. Schmid-Elsaesser R, Kunz M, Zausinger S, Prueckner S, Briegel J, Steiger HJ: Intravenous magnesium versus nimodipine in the treatment of patients with aneurysmal subarachnoid hemorrhage: a randomized study. Neurosurgery 2006, 58:1054-1065. 11. Muroi C, Terzic A, Fortunati M, Yonekawa Y, Keller E: Magnesium sulphate in the management of patients with aneurysmal subarachnoid hemorrhage: a randomized, placebo-controlled, dose-adapted trial. Surg Neurol 2008, 69:33-39. 12. Wong GK, Poon WS, Boet R, Chan MT, Gin T, Ng SC, Zee B, IMASH investigators: Intravenous magnesium sulphate after aneurysmal subarachnoid hemorrhage: a multi-center phase III study. Stroke 2010, 41:921-926. 13. Westermaier T, Stetter C, Vince GH, Pham M, Tejon JP, Eriskat J, Kunze E, Matthies C, Ernestus RI, Solymosi L, Roosen K: Prophylactic intravenous magnesium sulfate for treatment of aneurysmal subarachnoid hemorrhage: a randomized placebo-controlled, clinical study. Crit Care Med 2010, 38:1284-1290. 14. Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL: Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke 2007, 38:2315-2321. 15. Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, Terbrugge KG, Macdonald RL, Diringer MN, Broderick JP, Drier JP, Roos YB: Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observation studies: proposal of a multidisciplinary research group. Stroke 2010, 41:2391-2395. 16. Dorhout Mees SM, Rinkel GJ, Feign VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J: Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2007, , 3: CD000277. 17. Zhao XD, Zhou YT, Zhang X, Zhuang Z, Shi JX: A meta-analysis of treating subarachnoid hemorrhage with magnesium sulfate. J Clin Neurosci 2009, 16:1394-1397. 18. Ma L, Lu WG, Zhang JM, Chen G, Fan J, Sheng HS: Magnesium sulphate in the management of patients with aneurysmal subarachnoid haemorrhage: a meta-analysis of prospective controlled trials. Brain Injury 2010, 24:730-735. 19. Wilson JTL, Pettigrew LEL, Teasdale GM: Structured interviews for the Glasgow Outcome Scale and Extended Glasgow Outcome Scale: guidelines for their use. J Neurotrauma 1998, 15:573-585. 20. Wilson JTL, Hareendran A, Grant M, Baird T, Schulz UG, Muir KW, Bone I: Improving the assessment of outcomes in stroke: use of a structural interview to assign grades on the modified Rankin Scale. Stroke 2002, 33:2243-2246. 21. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavanghan DJ, McQuay HJ: Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 1996, 17:1-12. 22. Macedo SK, Nuss RM, Pereira S, Siqueira CM, Siquerira SB, Lima DP: Effect of magnesium on prophylaxis of vasospasm, morbidity, and mortality in subarachnoid hemorrhage patients. Critical Care 2009, 13:P54. Wong et al. Critical Care 2011, 15:R52 http://ccforum.com/content/15/1/R52 Page 7 of 8 23. Prevedello DM, Cordeiro JG, de Morais AL, Saucedo NS Jr, Chen IB, Araujo JC: Magnesium sulfate: role as possible attenuating factor in vasospasm morbidity. Surg Neurol 2006, 65 Suppl 1:S1:14-S1:20. 24. Keller E, Muroi C: Magnesium sulfate for subarachnoid hemorrhage: a piece of the mosaic. Stroke 2010, 41:e576, author reply e577. 25. Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang DA, Nelson R, Richards P, Sinar J, Bailey S, Skene A: Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ 1989, 298:636-642. 26. Higgins JP, Altman DG, (editors): Assessing risk of bias in included studies. In Cochrane Handbook for Systemic Reviews of Interventions. Edited by: Higgins JP, Green S. Chichester (UK): John Wiley 2008. 27. Hopyan J, Ciarallo A, Dowlatshahi D, Howard P, John V, Yeung R, Zhang L, Kim J, MacFarlane G, Lee TY, Aviv RI: Certainty of stroke diagnosis: incremental benefit with CT perfusion over noncontrast CT and CT angiography. Radiology 2010, 255:142-153. 28. Wong GK, Poon WS, Boet R, Chan MT, Gin T, Ng SC, Zee B, IMASH investigators: Plasma magnesium concentrations and clinical outcomes in aneurysmal subarachnoid hemorrhage patients: post-hoc analysis of Intravenous Magnesium Sulphate for Aneurysmal Subarachnoid Hemorrhage (IMASH) Trial. Stroke 2010, 41:1841-1844. 29. Kreiter KT, Mayer SA, Howard G, Knappertz V, Ilodigwe D, Sloan MA, Macdonald RL: Sample size estimates for clinical trials of vasospasm in subarachnoid hemorrhage. Stroke 2009, 40:2362-2367. 30. van den Bergh WM: Magnesium in subarachnoid haemorrhage: proven beneficial? Magnes Res 2009, 22:121-126. doi:10.1186/cc10017 Cite this article as: Wong et al.: Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage: an updated systemic review and meta-analysis. Critical Care 2011 15:R52. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Wong et al. Critical Care 2011, 15:R52 http://ccforum.com/content/15/1/R52 Page 8 of 8 . Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage: an updated systemic review and meta-analysis. Critical Care 2011 15:R52. Submit your next manuscript to BioMed Central and take. Intravenous Magnesium Sulphate for Aneurysmal Subarachnoid Hemorrhage trial; MASH: Magnesium and Acetylsalicylic Acid in Subarachnoid Hemorrhage trial; MASH: Magnesium and Acetylsalicylic Acid in Subarachnoid. Access Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage: an updated systemic review and meta-analysis George KC Wong 1* , Ronald Boet 2 , Wai S Poon 1 , Matthew TV Chan 3 , Tony Gin 3 ,